The glutamate system as a primary mediator of psychiatric pathology and a pathway for antidepressant action. New biomarkers and targets for treatment

Glutamate neurotransmission dysfunction is increasingly considered a core feature of mental illnesses. For over half a century the conceptual framework of research on these disorders has been dominated by the monoamine hypothesis, on which most of the drugs developed for clinical therapy are based. Although it was not acknowledged as a neurotransmitter until the early 1980s, glutamate has been later recognized as the major excitatory neurotransmitter in the brain, with glutamatergic neurons representing about 80% of total neurons in neocortex. In the past decade it has become increasingly acknowledged that maladaptive changes in the structure and function of excitatory/inhibitory circuitry (representing the vast majority of neurons and synapses in brain) have a primary role in the pathophysiology of mood and anxiety disorders, particularly major depression. Indeed, clinical research has shown alterations in levels, clearance and metabolism of glutamate in mood and anxiety disorders, and consistent volumetric changes in brain areas where glutamate neurons and synapses predominate. In parallel, preclinical studies with rodent stress and depression models have found dendritic remodeling and synaptic spines reduction in corresponding areas, suggesting these changes are major factors in psychopathology. Converging evidence from various groups, including ours, has shown that enhancement of glutamate release/transmission in cortical/limbic areas, in turn induced by stress and glucocorticoids, is crucial for these structural/functional changes. In addition, antidepressants are able to prevent the enhancement of glutamate release induced by acute stressors. Additional studies have shown that antidepressants may partly reverse the maladaptive changes in synapses/circuitry in stress and depression animal models. Furthermore, recent compelling evidence has shown that the glutamate system is also a target for rapid acting antidepressants, such as NMDA receptor antagonists. Building up on this large body of evidence, it will be shown how recent preclinical and clinical works can suggest novel biomarkers for pathology and targets for pharmacological intervention at the level of glutamate synapses and circuitry.